Preservative ophthalmic preparations

Preservatives are added to various dosage forms and cosmetic preparations to prevent microbial contamination. In parenteral and ophthalmic preparations, preservatives arc used to maintain. sterility in the event of accidental contamination during use. An ideal prc.scrvative would be effective at low concentrations against all possible microorganisms, be nontoxic and compatible with other constituents of the preparation, and be stable for the. shelf life of the preparation. The ideal pre.servative dues not exi.st. but there is quite a bit of experience with some of them. In srnne ca.ses. combinations of preservative agents arc used to approximate a mixture of ideal features. 

Inactive ingredients may be found in some preparations. Examples of these drugs include preservatives, antioxidants, which prevent deterioration of the product, and drugs that slow drainage of the drug from the eye into the tear duct. Examples of the types of eye preparations are found in the Summary Drug Table Select Ophthalmic Preparations. 

Sterility testing is conducted on each lot of ophthalmic product by suitable procedures, as set forth in the appropriate pharmacopeia and validated in each manufacturer s laboratory. While the majority of ophthalmic preparations contain preservatives for multiple-dose use, sterile preparations in special containers for individual use on a single patient must be made available. This availability is especially critical for every hospital, office, or other installation where accidentally or surgically traumatized eyes are treated, as well as for patients intolerant to preservatives. 

This preservative is comparatively new to ophthalmic preparations and is a polymeric quaternary ammonium germicide. Its advantage over other quaternary ammonium seems to be its inability to penetrate ocular tissues, especially the cornea. It has been used at concentrations of 0.001-0.01% in contact lens solutions as well as dry eye products. At clinically effective levels of preservative, POLYQUAD is approximately 10 times less toxic than benzalkonium chloride [87,137], Various in vitro tests and in vivo evaluations substantiate the safety of this compound [137,141,142], This preservative has been extremely useful for soft contact lens solutions because it has the least propensity to adsorb onto or absorb into these lenses, and it has a practically nonexistent potential for sensitization. Its ad-sorption/absorption with high water and high ionic lenses can be resolved by carefully balancing formulation components [143],... 

Topical and Ophthalmic Preparations Appearance (clarity, color, and especially homogeneity), odor, pH, resuspendability, consistency, particle size, weight loss (of more importance if plastic containers are used). Sterility and preservative levels also must be considered if the product is intended for ophthalmic administration. 

In ophthalmic preparations, benzalkonium chloride is one of the most widely used preservatives, at a concentration of 0.01-0.02% w/v. Often it is used in combination with other preservatives or excipients, particularly 0.1% w/v disodium edetate, to enhance its antimicrobial activity against strains of Pseudomonas. 

Chlorobutanol is primarily used in ophthalmic or parenteral dosage forms as an antimicrobial preservative at concentrations up to 0.5% w/v see Section 10. It is commonly used as an antibacterial agent for epinephrine solutions, posterior pituitary extract solutions, and ophthalmic preparations intended for the treatment of miosis. It is especially useful as an antibacterial agent in nonaqueous formulations. Chlorobutanol is also used as a preservative in cosmetics [see Section 16) as a plasticizer for cellulose esters and ethers and has been used therapeutically as a mild sedative and local analgesic. 

Methylparaben and other parabens are widely used as antimicrobial preservatives in cosmetics and oral and topical pharmaceutical formulations. Although parabens have also been used as preservatives in injections and ophthalmic preparations, they are now generally regarded as being unsuitable for these types of formulations owing to the irritant potential of the parabens. These experiences may depend on... 

Richards RME, McBride RJ. Phenylethanol enhancement of preservatives used in ophthalmic preparations. / Pharm Pharmacol 1971 23 141S-146S. 

Kohn SR, Gershenfeld L, Barr M. Effectiveness of antibacterial agents presently employed in ophthalmic preparations as preservatives against Pseudomonas aeruginosa. J Pharm Set 1963 52 967-974. 

Phenylmercuric acetate is no longer permitted to be used as a pesticide in the USA. It is, however, included in the FDA Inactive Ingredients Guide (ophthalmic preparations), and is also included in nonparenteral medicines licensed in the UK. In France, a maximum concentration of 0.01% is permitted for use in pharmaceuticals. The use of phenylmercuric acetate in cosmetics is restricted in the UK see Phenylmercuric Nitrate. Included in the Canadian List of Acceptable Non-medicinal Ingredients (however, there must be no other suitable preservatives available). 

Phenylmercuric salts are used as antimicrobial preservatives mainly in ophthalmic preparations, but are also used in cosmetics see Section 16), parenteral, and topical pharmaceutical formulations see Table I. 

Benzalkonium chloride is used mainly as a disinfectant for pre-operative skin cleansing and, surgical instruments but has sometimes been used in the treatment of ulcers, wounds and infected dermatoses. It is also present as a preservative in many cosmetic products and ophthalmic preparations. Irritation is strongly related to the concentration of the solution. 

When formulating aqueous ophthalmic preparations attention should be given to osmolality, pH, solubility, chemical interactions, stability of the active substance, together with viscosity and the choice of a preservative. Sterility is of critical importance and therefore the most appropriate sterilisation method must be chosen. 

An overview of preservatives is given in Sect. 23.8. More information concerning specific preservatives suitable for ophthalmic preparations can be found in the literature [66, 72, 88, 93, 94]. Benzalkonium chloride is the most frequently used preservative in ophthalmic products. However its use is under discussion, because of its toxicity in chronic treatment [95, 96]. Therefore new preservatives are used in the development of licensed products [94, 97-100]. 

In contrast, parenteral suspensions have relatively low solids contents, usually between 0.5 and 5%, with the exception of insoluble forms of penicillin in which concentrations of the antibiotic may exceed 30%. These sterile preparations are designed for intramuscular, intradermal, intralesional, intraarticular, or subcutaneous injection. Syringeability is an important factor to be taken into consideration with injectable dosage forms. The viscosity of a parenteral suspension should be sufficiently low to facilitate injection. Common suspending vehicles include preserved isotonic saline solution or a parenterally acceptable vegetable oil. Ophthalmic and optic suspensions that are instilled into the eye/ear must also be prepared in a sterile manner. The vehicles are essentially isotonic and aqueous in composition. The reader should refer to Chapter 12 for further discussion on parenteral products. 

Although some types of pharmaceutical products, like ophthalmic and injectable preparations, are sterilized by physical methods, including autoclaving, dry heat, or by bacterial filtration during their manufacture, many of them additionally require the presence of an antimicrobial preservative to maintain their aseptic condition throughout the period of their storage and use. Other types of preparations that are not sterilized during their... 

Bacterial keratitis Bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products has been reported. Serious damage to the eye and subsequent loss of vision may result from using contaminated preparations. Benzalkonium chloride Benzalkonium chloride is a preservative used in some of these products that may be absorbed by soft contact lenses. Patients wearing soft... 

Patients with a reported history of allergic responses to ester and amide anesthetics pose a challenge, especially when regional anesthesia is necessary. Two alternatives may be considered when minor ophthalmic surgical procedures are performed. A 1% solution of diphenhydramine may be prepared by diluting the 5% solution (Benadryl Steri-Vials) with sterile saline. Additionally, injecting preserved sterile saline alone has been shown to be effective for superficial surgical procedures such as papilloma removal and shave biopsies. 

Liquid dosage forms. The liquid products are prepared by dissolving the ingredients in the appropriate solvent systems. Dyes, flavors, sweeteners, and antimicrobial preservatives are added to mask unpleasant taste or appearance, and to prevent mold and bacterial growth. The final products are stored in large tanks before final packaging. If the liquid is used for injection or ophthalmic use, the liquid must be sterilized. Solutions for external or oral use do not require sterilization but generally contain antimicrobial preservatives [16, 17]. 

The other three classes of preservatives have been widely used in ophthalmic, nasal, and parenteral products, but not frequently in oral liquid preparations. The neutral preservatives are volatile alcohols their volatility introduces problems of odor and loss of preservative on aging in multidose preparations. The mercurials and quaternary ammonium compounds are excellent preservatives but are subject to incompatibilities.Mercurials are readily reduced to free mercury, and the quaternary compounds are inactivated by anionic substances. 

Benzethonium chloride is a quaternary ammonium compound used in pharmaceutical formulations as an antimicrobial preservative. Typically, it is used for this purpose in injections, ophthalmic and otic preparations at concentrations 0.01-0.02% w/v. Benzethonium chloride may also be used as a wetting and solubilizing agent, and as a topical disinfectant. 

Chlorocresol is used primarily as a preservative in topical pharmaceutical formulations but has also been used in nebulized solutions and ophthalmic and parenteral preparations. It should not, however, be used in formulations for intrathecal, intracisternal, or peridural injection. 

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